Objective
To assess the four-year clinical efficacy of IntraMuscular (IM) IFN-ß-1a in patients with Relapsing MS from the European IFN-ß-1a Dose-Comparison Study.

Methods
Patients who completed 36 months of treatment (Part 1) of the European IFN-ß-1a Dose-Comparison Study were given the option to continue double-blind treatment with IFN-ß-1a 30 mcg or 60 mcg IM once weekly (Part 2).

Analyzes of 48-month data were performed on sustained disability progression, relapses, and Neutralizing AntiBody (NAB) formation.

Results
Of 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. (Avonex) IFN-ß-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months.

There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48% and 43%, respectively), and annual relapse rates.

Relapses tended to decrease over 48 months. The incidence of patients who were positive for NABs at any time during the study was low in both treatment groups.

Conclusion
Compared with 60-mcg IM IFN-ß-1a once weekly, a dose of 30 mcg IM IFN-ß-1a once weekly maintains the same clinical efficacy over four years.

Conclusion
In RRMS, once weekly IFN-ß-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen.

In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN-ß-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.

#3

A Post-Marketing Study On Interferon-beta-1b And -1a Treatment In Relapsing/Remitting Multiple Sclerosis: Different Response In Drop-Outs And Treated Patients

Background
Interferon-beta-1b (Betaferon) and Interferon-beta-1a (Avonex) were licensed in Italy for treating Relapsing/Remitting Multiple Sclerosis in February 1996 and August 1997, respectively.

Objectives
To evaluate the effectiveness of these agents on the basis of clinical experience in northern Italian Multiple Sclerosis centres.

Design
Clinical data on patients with Relapsing/Remitting Multiple Sclerosis were collected on an appropriate form from 65 centres in northern Italy.

Intention to treat analysis was not possible, so patients who discontinued treatment (drop-outs) and who continued treatment (treated) were analyzed separately.

The main outcome measures were annual relapse frequency, number of relapse-free patients, mean change in Extended Disability Status Scale Score (EDSS), and number of patients who worsened.

Results
1481 patients were included; 834 were treated with Betaferon and 647 with Avonex for mean periods of 21.4 and 12.0 months, respectively.

Basal EDSS was 2.37 and 2.17, respectively, and relapse frequency was 1.62 and 1.45. The annual relapse rate decreased by more than 60% with Betaferon and 55% with Avonex. The proportions of relapse-free, improved, and worsened patients were similar in the two groups.

More patients interrupted treatment with Betaferon (41.1%) than with Avonex (15.3%); such patients showed more active disease at baseline and during treatment. The incidence of side effects was higher in Betaferon treated patients.

Conclusions
The effectiveness of Betaferon and Avonex is confirmed. There was a more marked effect than expected from the experimental trial results.

Dose And Frequency Of Interferon Treatment Matter: INCOMIN And OPTIMS

Three different Interferon-beta (IFN-ß) products are currently approved for the treatment of patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

However, the recommended method of administration, the dosage and the frequency of administration differ widely between each of the three products.

Although controlled clinical trials have demonstrated the efficacy of both alternate-day IFN-ß-1b (Betaferon/Betaseron) and once-weekly IFN-ß-1a (Avonex) compared with placebo.

It is likely that patient compliance, efficacy and tolerability are affected by the dosage regimen used. There are several issues to consider.

Once-weekly administration may be associated with fewer adverse events and greater convenience, and it has been suggested that this may increase compliance. Conversely, frequent administration may be associated with increased overall efficacy.

There is a convincing pharmacological rationale indicating that frequent dosing, with an interval of less than 72 h, is necessary to sustain the activity of IntraCellular Molecular Signalling Pathways responsible for regulating IFN-ß-induced Gene expression.

However, there was a need to explore the overall effectiveness of the two administration protocols in a comparative trial.

INCOMIN demonstrated convincingly that clinical and MRI outcome measures were significantly better in the IFN-ß-1b-treated group.

Blinded MRI evaluation confirmed the clinical results. Despite some limitations of the study design, imposed by the ethical and practical challenges of conducting comparative trials of injectable therapies.

The concordance of the clinical and MRI findings indicate that frequently administered IFN-ß-1b reduced evidence of disease activity more effectively than once-weekly administered IFN-ß-1a, with the clinical benefits for patients becoming more pronounced over time.

Given that the response to IFN-ß appears to be dose dependent, the question that might be asked is whether greater efficacy can be obtained by increasing doses beyond those currently approved.

OPTIMS (Optimization of Interferon dose for MS) is currently examining the safety and efficacy of a dose of IFN-ß-1b that is higher than any currently marketed IFN-ß. While OPTIMS is still underway, preliminary safety analyzes indicate that higher doses are well tolerated.

#5

A Retrospective, Observational Study Comparing The Four Available ImmunoModulatory Treatments For Relapsing/Remitting Multiple Sclerosis

The different treatment groups were similar in baseline demographic and clinical variables.

A significant fall in the annual relapse rate was observed for all four treatments, with the largest effect observed with Glatiramer Acetate (81% reduction in relapse rate, compared with pre-treatment values).

The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 37% in untreated patients to 83% in the Glatiramer Acetate treated group. No statistically significant changes in disability scores were observed over the treatment period.

This first such comparative study in Latin America shows that treatment of Multiple Sclerosis patients with ImmunoModulatory therapies in the context of current standards of care in Argentina provides clinically important benefit, and suggest that some of these therapies may be better than others.

Background
Interferon-beta (IFN-ß) is available in parenteral formulations for treatment of Multiple Sclerosis (MS).

The purpose of this study was to evaluate safety, tolerability and effects on MRI lesions of three different doses of oral IFN-ß-1a compared with placebo over six months in Relapsing/Remitting (RR) MS patients.

Methods
In this multicenter; double-blind randomized trial, RR-MS patients received 0.06, 0.6 or 6 million international units (MIU) IFN-ß-1a or placebo every other day for up to six months.

Gadolinium DTPA-enhanced Brain MRI scans were performed at screening and monthly during treatment.

The primary variable was the cumulative number of newly active lesions. Secondary variables included volume of enhancing lesions on T1-weighted images each month and lesion volume on T2-weighted images at months three and six.

Management Of Multiple Sclerosis: Current Trials And Future Options

Purpose Of The Review
The present review of Multiple Sclerosis (MS) therapeutic trials published in 2002 is intended to assist the reader in understanding the most current advances in the care of their patients.

Recent Findings
A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of patients with MS.

Several short-term studies in Relapsing/Remitting MS have demonstrated that it is possible to complete head-to-head comparison trials of active agents in MS (e.g. without a placebo control group).

The findings of these trials remain open to interpretation and have generated considerable controversy, as expected.

A phase 3 trial [the International MS Secondary/Progressive Avonex Controlled Trial (IMPACT)] became the fourth study of the beta-Interferons (Interferon-beta-1a, in this case) to demonstrate a partial effect on disease activity in Secondary/Progressive MS.

Two trials demonstrated apparent partial efficacy for the anthrecenedione Mitoxantrone in active and Progressive MS.

Disappointing results were announced for a number of large pivotal trials, although those results have not yet been published (e.g. oral Glatiramer Acetate in Relapsing/Remitting MS, Glatiramer Acetate in Primary/Progressive MS, and IntraVenous ImmunoGlobulin in Secondary/Progressive MS).

Summary
The MS research community needs to determine how best to address two key unanswered questions. Is late clinical deterioration often or invariably tied to the initial Inflammatory/DeMyelinating phase of the disease?

What is the optimal research design to address whether current and future experimental strategies affect the later phases of MS (e.g. does early treatment delay or prevent clinical disability)?

#8

Beta-Interferon Treatment Does Not Always Slow The Progression Of Axonal Injury In Multiple Sclerosis

Progression of disability in Multiple Sclerosis (MS) appears related to Axonal damage, which is at least in part associated with White Matter lesions.

Beta-Interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of Axonal injury.

To test the feasibility of this conclusion, particularly in a population with relatively active disease, we used Magnetic Resonance Spectroscopy measures, to test whether BIFN can reverse or arrest progression of Axonal injury in patients with MS.

Eleven patients with a history of active (median, 1.5 relapses/year) Relapsing/Remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel Magnetic Resonance Spectroscopic measurements of relative concentrations of Brain N-AcetylAspartate (NAA).

A measure of Axonal integrity from a Central, predominantly White Matter Brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and White Matter water T2 relaxation time (p = 0.047) over 12 months.

Also consistent with a treatment effect, White Matter T2-HyperIntense lesion loads did not increase.

However, the Central White Matter NAA/Creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02).

For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006).

These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of Axonal injury.

Nonetheless, there appears to be a relationship between the rate of progression of Axonal Injury and relapse rate over the previous two years.

The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.

#9

Interferon-beta-1a For Secondary/Progressive Multiple Sclerosis

This non-systematic review identified four randomized trials that have tested the efficacy of Interferon-beta in Secondary/Progressive Multiple Sclerosis (SPMS). Two were trials of Interferon-beta-1a (IFN-ß-1a) and two of Interferon-beta 1b (IFN-ß-1b).

All have shown significant reductions in relapse rates and accumulation of new Magnetic Resonance Imaging (MRI) lesions, but only one trial (of IFN-ß-1b) showed significant slowing of disability progression.

Post hoc analyzes of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with Relapsing disease.

In one of the trials of IFN-ß-1a (the SPECTRIMS trial), the hazard ratio for progression in the treated Relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses.

In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not.

These observations have led to the recommendation in national guidelines that prescribing of IFN-ß in SPMS be limited to those patients who have had disabling relapses in the last 2 years.

These conclusions should be reviewed when the full results of all four trials have been published.

The EVIDENCE study was a direct comparative study of two dose regimens of Interferon-beta-1a (IFN-ß-1a) used in the treatment of Relapsing/Remitting Multiple Sclerosis (RRMS): 30 mcg IntraMuscularly once weekly (qw; n=338) and 44 mcg SubCutaneously three times weekly (tiw; n=339).

The study continued for an average of 64 weeks. The safety population consisted of all patients receiving at least one dose of study drug.

Clinical assessments occurred every 4 weeks for 24 weeks and then every 12 weeks. Blood tests for safety were taken at baseline and at weeks 4 and 12, and every 12 weeks thereafter.

Overall adverse events were more common with the 44 mcg tiw regimen (p=0.007), and were due predominantly to differences in injection-site reactions. The majority of adverse events were rated mild by investigators.

Hepatic and Haematological adverse events and asymptomatic laboratory abnormalities were more common with 44 mcg tiw (p < 0.001),with no difference seen for severe events.

Flu-like symptoms were more common with 30 mcg qw (p=0.031), were more severe and persisted for longer. Serious adverse events were comparable for both groups, as were drug discontinuations.

In conclusion, although adverse events were more common with high-dose, high-frequency IFN-ß therapy, differences were primarily for mild events and did not affect treatment adherence.

Based on superior clinical and Magnetic Resonance Imaging outcomes over an average of 64 weeks, coupled with modest safety differences, the risk-benefit ratio for IFN-ß therapy in RRMS favours the 44 mcg tiw regimen over this period of time.

Methods
In this multicenter, open-label, prospective clinical trial, 96 patients with Relapsing/Remitting MS received IFN-ß-1a 30 mcg intramuscularly once weekly for 2 years.

Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2.

Results
IFN-ß-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2.

Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFN-ß-1a treatment was well tolerated.

Conclusion
This study confirms and extends the beneficial clinical profile for IFN-ß-1a (Avonex) in Relapsing MS.

#12

An Examination Of The Results Of The EVIDENCE, INCOMIN, And Phase III Studies Of Interferon-beta Products In The Treatment Of Multiple Sclerosis

Background
Three Interferon-beta (IFN-ß) products are currently available for the treatment of Relapsing Multiple Sclerosis (MS).

Each of these agents showed effectiveness in the treatment of MS in the respective randomized, double-blind, placebo controlled Phase III trials.

However, there have been no randomized, double-blind, placebo-controlled trials directly comparing the efficacy and safety of these formulations.

Objective
The objective of this article was to compare the results of available comparative studies with the results of the pivotal Phase III trials of each IFN-ß product.

Methods
BIOSIS, Current Contents/Clinical Medicine, and MEDLINE were searched for English-language articles published from 1996 to the present comparing the efficacy and safety of IFN-ß formulations in the treatment of MS.

Articles or abstracts that reported the results of Phase III trials or studies directly comparing IFN-ß formulations in the treatment of Relapsing or Relapsing/Remitting MS were included in the review.

Results
Seven head-to-head studies were identified that directly compared the efficacy of IFN-ß products in the treatment of MS.

Two of these studies- INCOMIN (Independent Comparison of Interferon) and EVIDENCE (Evidence for Interferon Dose-Effect: European-North American Comparative Efficacy) - found significant differences in clinical efficacy between IFN-ß products, whereas the remaining studies showed equal clinical efficacy between products.

Conclusion
Inconsistencies within and between the results of the reviewed studies suggest that clinicians should use caution in interpreting the findings of the INCOMIN and EVIDENCE comparative trials.